Abstract
Background Drug-resistant tuberculosis (TB) remains a formidable global health challenge. Host-directed therapies (HDTs) offer the potential to mitigate tissue damage, reduce treatment duration, and improve clinical outcomes by modulating immune responses. We assessed the safety and potential efficacy of adjunctive ibuprofen—an inexpensive, well-tolerated non-steroidal anti-inflammatory drug—in patients with pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) TB.
Methods
In this prospective, open-label, randomized pilot study (NCT02781909) conducted in Georgia, 28 adults with bacteriologically confirmed pulmonary pre-XDR or XDR-TB were randomized 1:1 to receive either standard-of-care (SoC) TB treatment alone (n=14) or SoC plus 400 mg ibuprofen daily during the first 2 months (n=14). Participants were followed for 6 months. The primary endpoints were early sputum culture conversion and radiological improvement. Secondary endpoints included WHO-defined final treatment outcomes, safety, health-related quality of life (HQoL), and changes in inflammatory markers.
Findings By week 2, culture negativity was achieved in 27% of control participants versus 9% in the ibuprofen group (risk difference 18%, 95% CI −13 to 50). The median time to culture conversion was 4 months in both groups. At month 2, favourable X-ray evolution was observed in 64% of controls compared with 54% of the ibuprofen group (risk difference 9%, 95% CI −32 to 50), with 90% of participants in each group showing improvement by month 6. Final treatment outcomes were comparable (≈71% cured) and the incidence of safety-related events did not differ significantly. Notably, the ibuprofen group exhibited greater proportional reductions in inflammatory markers—including a statistically significant decrease in the monocyte-to-lymphocyte ratio at months 2 and 5, along with reductions in interferon gamma levels and the enrichment score for Thompson_FAIL_13 gene signature at month 6.
Interpretation Although adjunctive ibuprofen did not improve primary microbiological or radiological endpoints, its excellent safety profile and significant anti-inflammatory effects support its potential role as an immune-modulating adjunct in the treatment of drug-resistant TB. These findings warrant further investigation in larger studies to optimize dosing and evaluate clinical benefits.
Funding Catalan Government (2021 SGR 00920), Spanish Government-FEDER Funds (CPII18/00031, PI20/01424 and CB06/06/0031, and European Union’s Horizon 2020 research and innovation program under grant agreement No. 847762 (SMA-TB project).
Evidence before this study Drug-resistant tuberculosis (TB) remains a major global health challenge. Host-directed therapies (HDTs) have emerged as a means to shorten treatment, improve outcomes and limit tissue damage from excessive inflammation. In preclinical models of active TB, non-steroidal anti-inflammatory drugs (NSAIDs) enhanced bacterial control and reduced lung pathology. Clinical data on NSAIDs as HDTs are scarce, confined to small studies in tuberculous meningitis and TB patients with diabetes, which reported encouraging but preliminary benefits.
Added value of this study This is the first randomized trial of adjunctive ibuprofen in patients with pre-XDR and XDR-TB. Whilst ibuprofen did not confer microbiological or clinical benefit at two and six months, it was safe, well tolerated and significantly lowered systemic inflammatory markers. Baseline imbalances in disease severity and high inter-patient variability likely obscured any clinical effect despite reduced inflammation.
Implications of all the available evidence Our findings demonstrate that ibuprofen is a safe adjunct in drug-resistant TB and can mitigate harmful inflammation. Future work should explore optimised dosing regimens, alternative HDT candidates and more sensitive or tailored endpoints—potentially focusing on patient subgroups most likely to benefit. Such refinements will be essential to reveal the true clinical value of HDTs across diverse TB populations.
Competing Interest Statement
JMGI, CS, and JF were employees of Anaxomics Biotech S.L., Barcelona, during part of the study. CS and JF are now at IGTP, Badalona, and JMGI is at VHIR, Barcelona. CV declares receiving funding for the present study (2021 SGR 00920, CPII18/00031, PI20/01424, CB06/06/0031, and SMA-TB project (GA 847762), all paid to her institution. She is also a non-paid board member of 2 NPO: the foundation FUITB (http://www.uitb.cat/fuitb/) and ACTMON foundation (http://www.actmon.org/index.php), and the Secretary of TB & NTM group of the European Respiratory Society Assembly 10.
Clinical Trial
NCT02781909
Funding Statement
This study received support from: -the Catalan Government (through 2021 SGR 00920)-the Spanish Government-FEDER Funds (through CPII18/00031, PI20/01424 and the CIBER Enfermedades Respiratorias (CB06/06/0031)) -the European Union Horizon 2020 research and innovation program under grant agreement No. 847762 (SMA-TB project). JMGI and CS acknowledge funding from the European Union Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 859962 and No 956148, respectively.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Ethics approval for this study was granted by the Ethics review Committee of National Center for Tuberculosis Lung Diseases of Tbilisi,Georgia, where the trial was conducted.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
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Data Availability
To submit inquiries related to NSAIDS-XDR-TB clinical research, or to request access to individual participant data associated, please contact corresponding author. RNA seq data has been submitted to the GEO database (accession number pending).